Inhalable medicament

ABSTRACT

The present invention provides a solution formulation for inhalation comprising: a liquid phase; an active ingredient containing a carboxylic ester in which the oxygen atom is covalently bound to a quaternary nitrogen-containing heterocycle, dissolved in the liquid phase; and a magnesium or calcium salt, dissolved in the liquid phase. The formulation is particularly suited to pMDIs and nebulisers.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims priority to U.S. Provisional Application No.61/907,778, filed Nov. 22, 2013, the entire disclosure of which isincorporated herein by reference for all purposes.

FIELD OF THE INVENTION

The present invention relates to an inhalable medicament and morespecifically to a solution formulation comprising an active ingredientsusceptible to chemical degradation.

DISCUSSION OF THE RELATED ART

A number of active ingredients commonly used in inhalation therapy andin particular in maintenance bronchodilator treatment to relievesymptoms of patients with asthma and chronic obstructive pulmonarydisease (COPD) have structures based around quaternary derivatives ofatropine. These active ingredients tend to belong to a class ofcompounds known as antimuscarinic agents, which are compounds thatoperate on the muscarinic acetylcholine receptors.

Atropine has the structure:

Atropine is based around a carboxylic ester in which the oxygen atom iscovalently bound to a nitrogen-containing heterocycle. The quaternaryderivatives of atropine which have subsequently been developed containthe carboxylic ester in which the oxygen atom is covalently bound to aquaternary nitrogen-containing heterocycle.

Common examples of active ingredients having this functionality aretiotropium (1), ipratropium (2), glycopyrronium (3), oxitropium (4),aclidinium (5) and trospium (6). The structures of these activeingredients are depicted below, where X⁻ has been added to denote thecounterion.

Various approaches have been used for formulating inhalable medicaments,including dry powder inhaler (DPI) formulations, pressurised metereddose inhaler (pMDI) formulations and nebuliser formulations. The purposeof an inhalable formulation is to present the formulation in the form ofan aerosol of particles having a particle size suitable for lungdeposition (typically a mass median aerodynamic diameter (MMAD) of 1-5microns). In the case of a liquid formulation, aerosolisation formsdroplets of drug dissolved or suspended in the droplets, followed byfull or partial evaporation of the liquid phase leading to particleshaving a size suitable for lung deposition (MMAD as above).

Typically, approaches which use dry powders suffer from the drawbackthat only a small portion of the powdered active ingredient is actuallyinhaled into the lungs.

pMDIs and nebulisers are generally more efficient. pMDI and nebuliserformulations may be presented as suspensions or solutions. In a solutionformulation, the active ingredient is dissolved in a liquid phase—ahydrofluoroalkane (HFA) propellant for pMDIs or an aqueous phase fornebulisers.

Drawbacks associated with suspensions are potential blockage of the pMDIdispensing nozzle orifice, physical instability of the suspendedparticles and the requirement to use suspending agents such assurfactants. Solution formulations are easier to manufacture and do notsuffer from the above-described drawbacks. However, a significantproblem associated with formulating active ingredients as a solutionformulation is that active ingredients are chemically more reactive insolution than they are in the solid phase. This is a particular problemfor active ingredients containing a carboxylic ester in which the oxygenatom is covalently bound to a quaternary nitrogen-containingheterocycle, because they are particularly sensitive to chemicaldegradation, particularly hydrolysis or solvolysis of the ester leadingto de-esterification and/or trans-esterification (by reaction with anyalcohols present in the liquid phase, e.g., ethanol).

Therefore, there remains a need in the art for solution formulations ofsuch active ingredients with increased chemically stability.

SUMMARY OF THE INVENTION

Accordingly, the present invention provides a solution formulation forinhalation comprising:

a liquid phase; an active ingredient containing a carboxylic ester inwhich the oxygen atom is covalently bound to a quaternarynitrogen-containing heterocycle, dissolved in the liquid phase; and amagnesium or calcium salt, dissolved in the liquid phase.

That is, quaternary derivatives of atropine in solution have beenunexpectedly found to be stabilised by dissolved magnesium and calciumsalts.

DESCRIPTION OF THE DRAWING

FIG. 1 shows the results of a degradation study using tiotropiumbromide.

DETAILED DESCRIPTION OF CERTAIN EMBODIMENTS OF THE INVENTION

The present invention will now be described with reference to theaccompanying drawing, in which FIG. 1 shows the results of a degradationstudy using tiotropium bromide.

The formulation of the present invention contains an active ingredientcontaining a carboxylic ester in which the oxygen atom is covalentlybound to a quaternary nitrogen-containing heterocycle. As previouslyexplained, these active ingredients are conceptually related toatropine, but contain a quaternary nitrogen atom (i.e. a quaternaryammonium cation). The quaternary nitrogen-containing heterocycle istypically saturated. It may be mono-, bi- or tri-cyclic. The activeingredient may also have a hydroxyl group in the α- or β-position withrespect to the ester carbonyl carbon atom, more particularly theα-position.

Preferably, the active ingredient is selected from tiotropium,ipratropium, glycopyrronium, oxitropium, aclidinium and trospium. Morepreferably, the active ingredient is a bromide salt of these activeingredients, e.g., tiotropium bromide.

The amount of the active ingredient present will vary depending on thedose of active ingredient that is required for the particular product,medical indication and patient. Typically, the amount of activeingredient is from 0.001-0.4 wt %, based on the total weight of theformulation and more preferably 0.005-0.1 wt %, based on the totalweight of the formulation.

The formulation of the present invention also contains a magnesium orcalcium salt. This salt is dissolved in the liquid phase and hence is asoluble salt. The formulation provides a homogeneous phase containing,inter alia, the salt. Preferably, the salt is selected from magnesiumchloride, magnesium citrate, calcium chloride and calcium citrate(although magnesium citrate is less preferred for HFA formulationsbecause it is harder to dissolve in such formulations), more preferablyfrom magnesium chloride and calcium chloride, and most preferably, thesalt is magnesium chloride. The amount of salt is preferably from 0.0001to 0.01 wt %, based on the total weight of the formulation. Morepreferably, the amount of salt is from 0.001 to 0.005 wt %, based on thetotal weight of the formulation. The salt provides the requiredstability to the active ingredient when in solution.

The molar ratio of the active ingredient (based on the cation) to salt(based on the magnesium or calcium) is preferably 1:0.5 to 1:3.

Accordingly, the present invention also provides for the use of amagnesium or calcium salt in a solution formulation for inhalation, forthe stabilisation of an active ingredient containing a carboxylic esterin which the oxygen atom is covalently bound to a quaternarynitrogen-containing heterocycle.

The formulation of the present invention is a solution formulation andhence the active ingredient, the salt and the liquid phase form a singlehomogeneous phase. The active ingredient and the salt are dissolved inthe liquid phase. Therefore, the active ingredient and the salt must besoluble in the liquid phase. Preferably, the formulation can be cooledto 4° C. and then re-heated to ambient temperature without precipitationof the active ingredient. The present invention does not preclude othercomponents being present in the formulation including components whichare not in solution, e.g., other active ingredients which are present insuspended form.

The formulation of the present invention described herein may be a pMDIor a nebuliser formulation. That is, the formulations of the presentinvention can be used in pMDIs and/or nebulisers.

When the formulation according to the present invention is for a pMDI,the liquid phase comprises an HFA propellant. HFA propellants are wellknown in the art. The preferred HFAs of the present invention are HFA134a and/or HFA 227, most preferably HFA 134a.

When the formulation according to the present invention is for a pMDI,the liquid phase may additionally comprise a co-solvent. Suitableexamples of co-solvents are water, alcohols having 1 to 3 carbon atoms,alkanes having 3 to 6 carbon atoms and dialkyl ethers having 2 to 4carbon atoms. Specific examples of suitable co-solvents are water,ethanol, propanol, isopropanol, ethylene glycol, propylene glycol,glycerol, propane, butane, isobutane, pentane, dimethyl ether anddiethyl ether.

The co-solvent preferably comprises ethanol, water and/or glycerol. Morepreferably, the co-solvent comprises ethanol. In a particularlypreferred embodiment, the co-solvent comprises ethanol and water. Mostpreferably, the co-solvent comprises ethanol, water and glycerol.

When the co-solvent comprises ethanol, the ethanol is preferablydehydrated ethanol. The ethanol is principally present to solubilise theactive ingredient. In a preferred embodiment, the amount of ethanol is 5to 25 wt %, more preferably 10 to 20 wt %, based on the total weight tothe formulation.

When the co-solvent comprises water, the water is preferably water forinhalation. The water is preferably present at 0.1 to 1.0 wt % and morepreferably 0.3 to 0.7 wt %, based on the total weight to theformulation.

When the co-solvent comprises glycerol, the glycerol is present at 0.5to 2.0 wt %, based on the total weight to the formulation. For someapplications, the droplet sizes of the active ingredient dissolved inthe liquid phase will be too small for optimal lung deposition. In suchcases, glycerol may be added to the formulation. Glycerol is lessvolatile than most co-solvents used in solution formulations accordingto the present invention (for example, ethanol) and hence experiencesless evaporation on actuation, thereby providing larger droplets (bylarger is meant that they have a higher MMAD).

In a preferred embodiment, the formulation comprises tiotropium bromide,ethanol, glycerol, water, citric acid, magnesium chloride and an HFApropellant.

On actuation of a pMDI, a metered dose of the formulation is releasedfrom the inhaler. The metered dose of the formulation passes through avalve stem and stem block where it is discharged via an orifice in adispensing nozzle of the stem block into a mouthpiece and hence to thepatient. On release, most of the liquid phase rapidly evaporates Theparticle size of the emitted particles will depend on a number offactors, including the size of the orifice in the dispensing nozzle, thespray force, the plume geometry, the precise amount of co-solvent used(if present), etc. Typically, however, the particles will be less than 5microns in diameter (MMAD).

It should be noted that MMADs may be measured using a next-generationimpactor (NGI).

pMDIs are well known in the art; see, for example, Drug Delivery to theRespiratory Tract, Eds. D. Ganderton and T. Jones, VCH Publishers, 1987,pages 87-88, or Pharmaceutics—The Science of Dosage Form Design, SecondEdition, Ed. M. E. Aulton, Churchill Livingstone, 2002, page 476 et seqfor details.

pMDIs typically have a medicament-containing canister and an actuatorhousing having a mouthpiece. The canister is usually formed from analuminium cup having a crimped lid which carries a metering valveassembly. The metering valve assembly is provided with a protrudingvalve stem which is inserted as a push fit into the stem block in theactuator housing.

To actuate, the user applies a compressive force to the closed end ofthe canister. The internal components of the metering valve assembly arespring loaded so that, typically, a compressive force of 15 to 35 N isrequired to activate the device. In response to this compressive force,the canister moves axially with respect to the valve stem by an amountvarying between about 2 and 4 mm. This degree of axial movement issufficient to actuate the metering valve and cause a metered quantity ofthe formulation to be expelled through the valve stem. This is thenreleased into the mouthpiece via an orifice in the dispensing nozzle ofthe stem block. A user inhaling through the mouthpiece of the device atthis point will thus receive a dose of the active ingredient.

An inhalation-actuated inhaler (also known as breath-actuated inhaler)is particularly preferred in order to prevent inadvertent actuation intothe eye(s) of the patient. Suitable inhalers are disclosed in WO92/09323, GB 2 264 238 and WO 01/93933. When the formulation of thepresent invention is for a pMDI, the present invention most preferablyemploys the inhaler as described with reference to FIGS. 3-5 of WO92/09323.

The present invention further provides a pMDI comprising a canister,wherein the canister contains the solution formulation as describedherein. The canister is located in the actuator housing as discussedherein. The canister preferably contains 100 actuations or fewer,preferably about 60 actuations (i.e. a one-month supply, based on twoactuations per dose). This is a relatively low quantity and hence thehead space in the canister tends to be greater than with conventionalpMDIs which provides an increased tendency for the active ingredient todegrade chemically. However, even in this more challenging environment,the formulation of the present invention is able to provide the requiredlevel of chemical stability. For example, a 10 mL brim-full-capacitycanister may have a fill volume of 2.5 to 6.3 mL and a correspondingheadspace volume of 7.5 to 3.7 mL. The valve is preferably a 25 to 63microlitre valve, more preferably a 25 or 50 microlitre valve.

It has also been found that the formulation of the present invention isnot only capable of reducing or preventing chemical degradation of theactive ingredient, but also does not significantly affect the materialof the canister. This provides the significant advantage that anuncoated aluminium canister may be used, thereby reducing the costs ofthe pMDI without adversely affecting the formulation. Thus, according toa preferred embodiment of the present invention, the pMDI comprises acanister composed of uncoated aluminium, anodised aluminium (e.g., withhydrofluoric or nitric acid), or aluminium in which the internalsurfaces are coated with a fluorinated polymer (e.g., FEP or FCP), morepreferably uncoated aluminium.

When the formulation according to the present invention is for anebuliser, the liquid phase comprises water. Co-solvents may also bepresent, as described hereinabove with reference to pMDIs.

In a nebuliser, the solution is atomised in order to deliver droplets ofthe active ingredient in the liquid phase. Nebulisers are well known inthe art and further details may be found in, for example,Pharmaceutics—The Science of Dosage form Design” Second Edition, Ed. M.E. Aulton, Churchill Livingston, 2002. Nebulisers include soft-mistgenerating devices, such as Respimat®.

The formulation of the present invention may additionally comprisecitric acid. Citric acid has been found to provide additionalstabilisation in the presence of the salts. Preferably, the citric acidis present in 0.01 to 0.2 wt %, based on the total weight of theformulation.

The present invention further provides a nebuliser comprising areservoir, wherein the reservoir contains the formulation as describedherein.

As the formulation is a solution, the formulation does not require thepresence of surfactants (which are used to stabilise suspended particlesof the active ingredient in a suspension formulation). Accordingly, itis not necessary to add surfactant to the formulation and hence theformulation of the present invention is preferably substantially free ofsurfactant (e.g., the formulation contains less than 0.0001% by weightof surfactant).

The present invention will now be described with reference to thefollowing example, which is not intended to be limiting.

EXAMPLE

Batches of solution formulations were prepared by combining tiotropiumbromide, ethanol, water, glycerol and magnesium chloride (invention) ormanganese chloride (comparative) and mixing the components until asolution was formed. All formulations contained 0.015 wt % tiotropiumbromide and HFA 134a to 100 wt %. The solution was charged into acanister (as specified in Table 1) which was then sealed with a valve(as specified in Table 1) and filled with HFA 134a. The amounts of theexcipients are set out in the Table 1.

TABLE 1 Formulations for degradation studies Formulation (wt %)Tiotropium Batch bromide Ethanol Water Glycerol MnCl₂ MgCl₂ ValveCanister A 0.015 20 0.5 1.5 0.0005 0 BK361(RB700) AA* B 0.015 20 0.5 1.50.00025 0 BK361(RB700) AA* C 0.015 20 0.5 1.5 0 0 BK361(RB700) AA* D0.015 20 0.5 1.5 0 0 BK361(RB700) FEP** E 0.015 20 0.5 1.5 0 0.003BK361(RB700) AA* F 0.015 20 0.5 0 0 0 BK357(BK701) AA* *Anodisedaluminium **Fluorinated ethylene propylene

The results of degradation studies conducted at 50° C. are shown inFIG. 1. The impurities left to right within each batch are: knownimpurity A; known impurity B; known impurity TB-iso; known impurity E;known ethyl ester; total known impurities; total unknown impurities; andtotal known+unknown impurities. The known impurities are: A2-hydroxy-2,2-dithiophen-2-ylacetic acid; B(1R,2R,4S,5S,7s)-9-methyl-3-oxa-9-azatricyclo[3.3.1.0^(2,4)]nonan-7-yl2-hydroxy-2,2-dithiophen-2-ylacetate; C(1R,3s,5S)-3-[(2-hydroxy-2,2-dithiophen-2-ylacetyl)oxy]-8,8-dimethyl-8-azoniabicyclo[3.2.1]oct-6-enebromide; D (1R,3s,5S)-8-methyl-8-azabicyclo[3.2.1]oct-6-en-3-yl2-hydroxy-2,2-dithiophen-2-ylacetate; E methyl2-hydroxy-2,2-dithiophen-2-ylacetate; F dithiophen-2-ylmethanone; G(1R,2R,4S,5S,7s)-7-hydroxy-9,9-dimethyl-3-oxa-9-azoniatricyclo[3.3.1.0^(2,4)]nonanebromide; H(1s,3RS,4RS,5RS,7SR)-4-hydroxy-6,6-dimethyl-2-oxa-6-azoniatricyclo[3.3.1.0^(3,7)]nonane bromide; I(1R,2R,4S,5S,7r)-7-[(2-hydroxy-2,2-dithiophen-2-ylacetyl)oxy]-9,9-dimethyl-3-oxa-9-azoniatricyclo[3.3.1.0^(2,4)]nonanebromide; J(1R,3s,5S,8s)-8-(chloromethyl)-3-[(2-hydroxy-2,2-dithiophen-2-ylacetyl)oxy]-8-methyl-8-azoniabicyclo[3.2.1]oct-6-enechloride; and K(1R,2R,4S,5S,7s)-9-acetyl-3-oxa-9-azatricyclo[3.3.1.0^(2,4)]nonan-7-yl2-hydroxy-2,2-dithiophen-2-ylacetate.

The results show an acceptably low level of chemical degradation after 6weeks for batch E.

1. A solution formulation for inhalation comprising: a liquid phase; anactive ingredient containing a carboxylic ester in which the oxygen atomis covalently bound to a quaternary nitrogen-containing heterocycle,dissolved in the liquid phase; and at least one of a magnesium orcalcium salt, dissolved in the liquid phase.
 2. The formulation asclaimed in claim 1, wherein the active ingredient is selected from atleast one of tiotropium, ipratropium, glycopyrronium, oxitropium,aclidinium or trospium.
 3. The formulation as claimed in claim 1,wherein the active ingredient is tiotropium bromide.
 4. The formulationas claimed in claim 1, wherein the amount of active ingredient is from0.001-0.4 wt %, based on the total weight of the formulation.
 5. Theformulation as claimed in claim 1, wherein the salt includes at leastone of magnesium chloride, magnesium citrate, calcium chloride orcalcium citrate.
 6. The formulation as claimed in claim 1, wherein theamount of salt is from 0.0001 to 0.01 wt %, based on the total weight ofthe formulation.
 7. The formulation as claimed in claim 1, wherein theformulation is for a pressurised metered dose inhaler and the liquidphase comprises an HFA propellant.
 8. The formulation as claimed inclaim 7, wherein the liquid phase additionally comprises a co-solvent.9. The formulation as claimed in claim 8, wherein the co-solventcomprises ethanol.
 10. The formulation as claimed in claim 9, whereinthe formulation comprises tiotropium bromide, ethanol, glycerol, water,citric acid, magnesium chloride and an HFA propellant.
 11. Theformulation as claimed in claim 1, wherein the formulation is for anebuliser and the liquid phase comprises water.
 12. A metered doseinhaler comprising a canister, wherein the canister contains theformulation as claimed in claim
 1. 13. The metered dose inhaler asclaimed in claim 12, wherein the canister is composed of aluminium inwhich the internal surfaces are uncoated.
 14. A nebuliser comprising areservoir, wherein the reservoir contains the formulation as claimed inclaim
 1. 15. A method of stabilizing an active ingredient containing acarboxylic ester in which the oxygen atom is covalently bound to aquaternary nitrogen-containing heterocycle, wherein the activeingredient is present in a solution formulation for inhalation, themethod comprising formulating the solution formulation using at leastone of a magnesium salt or a calcium salt.
 16. A method of relievingsymptoms of a patient with asthma, comprising administering theformulation as claimed in claim 1 to the patient via inhalation.
 17. Themethod of claim 16, wherein the formulation is administered to thepatient using a metered dose inhaler comprising a canister and whereinthe canister contains the formulation.
 18. The method of claim 16,wherein the formulation is administered to the patient using a nebulizercomprising a reservoir and wherein the reservoir contains theformulation.
 19. The method of claim 16, wherein the amount of salt isfrom 0.0001 to 0.01 wt %, based on the total weight of the formulation.20. The method of claim 16, wherein the salt includes at least one ofmagnesium chloride, magnesium citrate, calcium chloride or calciumcitrate.
 21. A method of relieving symptoms of a patient with chronicobstructive pulmonary disease, comprising administering the formulationas claimed in claim 1 to the patient via inhalation.
 22. The method ofclaim 21, wherein the formulation is administered to the patient using ametered dose inhaler comprising a canister and wherein the canistercontains the formulation.
 23. The method of claim 21, wherein theformulation is administered to the patient using a nebulizer comprisinga reservoir and wherein the reservoir contains the formulation.
 24. Themethod of claim 21, wherein the amount of salt is from 0.0001 to 0.01 wt%, based on the total weight of the formulation.
 25. The method of claim21, wherein the salt includes at least one of magnesium chloride,magnesium citrate, calcium chloride or calcium citrate.